Axon swelling in BORC-depleted neurons. Mitochondria are in purple, and autophagosomes (vesicles in which cellular components are degraded) are in green.
Credit: Bonifacino Lab, NICHD
Within cells, BLOC-one-related complex (BORC) regulates the positioning of lysosomes, structures that break down unneeded or worn-out cell parts. The ability of lysosomes to move within cells is critical for many cellular functions, including those important for immunity, cell repair, cell migration, and cancer progression. Problems with lysosomes can also contribute to neurological diseases. Although BORC is present in all human cells, BORC deficiency primarily affects the central nervous system. Work by the Bonifacino Lab helps illuminate the mechanism by which BORC deficiency leads to neurodegeneration.
- The team found that halting lysosome transport in neurons by depleting BORC prevented trafficking of certain mRNAs into the axon, a part of the neuron that enables it to communicate with other nerve cells.
- Many of these mRNAs encode proteins important for the function of mitochondria—the cell’s energy producers.
- Decreased production of these mitochondrial proteins in the axon leads to defects in the mitochondria and eventually to degeneration of the axon.
- They also help explain how defects or deficiencies in BORC may contribute to neurodegenerative diseases, including a rare, infant-onset neurodegenerative disease caused by genetic variants that disable the protein BORCS8.
Reference
De Pace R, Ghosh S, Ryan VH, Sohn M, Jarnik M, Rezvan Sangsari P, Morgan NY, Dale RK, Ward ME, Bonifacino JS. Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration. Nature Neuroscience DOI: 10.1038/s41593-024-01619-1 (2024)
Learn more about the Cell and Structural Biology group: https://www.nichd.nih.gov/about/org/dir/affinity-groups/CSB
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